tbuckley/cabot-search huggingface dataset:
In vivo gene immunotherapy for cancer
Authors: David Mai, Carl H. June, Neil C. Sheppard
Journal: Science Translational Medicine (2022)

Cancer is becoming increasingly understood not only as a disease of pathological cells but also as one of immune hypofunction. The heterogenous and patient-specific nature of cancer further underscores the need for personalized cellular therapies, which are currently produced ex vivo. Gene-modulating approaches, such as therapeutic RNAs and improved viral vectors, now bring us closer toward strategies for mitigating disease, particularly for diseases that benefit from altering gene or transgene expression profiles in pathological or therapeutic immune cells. An advancing toolbox of technologies and trends toward simplifying personalized therapies foreshadow opportunities for direct, in vivo precision medicine against cancer.
Interleukin-2–based therapies in cancer
Authors: Miro E. Raeber, Dilara Sahin, Onur Boyman
Journal: Science Translational Medicine (2022)

Molecular insights into the mechanism of beneficial and adverse effects of interleukin-2 (IL-2) have resulted in the development of improved IL-2 formulations with IL-2 receptor bias and tissue-targeting properties. Several of these compounds are currently in clinical development and are ushering IL-2 therapy into the current era of cancer immunotherapy.
BLIMP1 and NR4A3 transcription factors reciprocally regulate antitumor CAR T cell stemness and exhaustion
Authors: In-Young Jung, Vivek Narayan, Sierra McDonald, Andrew J. Rech, Robert Bartoszek, Gwanui Hong, Megan M. Davis, Jun Xu, Alina C. Boesteanu, Julie S. Barber-Rotenberg, Gabriela Plesa, Simon F. Lacey, Julie K. Jadlowsky, Donald L. Siegel, Dana M. Hammill, Park F. Cho-Park, Shelley L. Berger, Naomi B. Haas, Joseph A. Fraietta
Journal: Science Translational Medicine (2022)

Chimeric antigen receptor (CAR) T cells have not induced meaningful clinical responses in solid tumors. Loss of T cell stemness, poor expansion capacity, and exhaustion during prolonged tumor antigen exposure are major causes of CAR T cell therapeutic resistance. Single-cell RNA-sequencing analysis of CAR T cells from a first-in-human trial in metastatic prostate cancer identified two independently validated cell states associated with antitumor potency or lack of efficacy. Low expression of PRDM1 , encoding the BLIMP1 transcription factor, defined highly potent TCF7 [encoding T cell factor 1 (TCF1)]–expressing CD8 + CAR T cells, whereas enrichment of HAVCR2 [encoding T cell immunoglobulin and mucin-domain containing-3 (TIM-3)]–expressing CD8 + T cells with elevated PRDM1 was associated with poor outcomes. PRDM1 knockout promoted TCF7 -dependent CAR T cell stemness and proliferation, resulting in marginally enhanced leukemia control in mice. However, in the setting of PRDM1 deficiency, a negative epigenetic feedback program of nuclear factor of activated T cells (NFAT)–driven T cell dysfunction was identified. This program was characterized by compensatory up-regulation of NR4A3 and other genes encoding exhaustion-related transcription factors that hampered T cell effector function in solid tumors. Dual knockout of PRDM1 and NR4A3 skewed CAR T cell phenotypes away from TIM-3 + CD8 + and toward TCF1 + CD8 + to counter exhaustion of tumor-infiltrating CAR T cells and improve antitumor responses, effects that were not achieved with PRDM1 and NR4A3 single knockout alone. These data underscore dual targeting of PRDM1 and NR4A3 as a promising approach to advance adoptive cell immuno-oncotherapy.
End-to-end P300 BCI using Bayesian accumulation of Riemannian probabilities
Authors: Quentin Barthélemy, Sylvain Chevallier, Raphaëlle Bertrand-Lalo, Pierre Clisson
Journal: Brain-Computer Interfaces (2022)

In brain–computer interfaces (BCI), most of the approaches based on event-related potential (ERP) focus on the detection of P300, aiming for single trial classification for a speller task, but leaving the character classification out of the scope. To reduce the number of repetitions while maintaining a good character classification, it is critical to embrace the full classification problem. We introduce an end-to-end pipeline, starting from feature extraction, and composed of an ERP-level classification using probabilistic Riemannian MDM which feeds a character-level classification using Bayesian accumulation of confidence across trials. Whereas existing approaches only increase the confidence of a character when it is flashed, our new pipeline, called Bayesian accumulation of Riemannian probabilities (ASAP), update the confidence of each character after each flash. We demonstrate that this seamless processing of information from signal to BCI characters performs significantly better than standard methods on public P300 datasets.
Uganda Genome Resource: A rich research database for genomic studies of communicable and non-communicable diseases in Africa
Authors: Segun Fatumo, Joseph Mugisha, Opeyemi S. Soremekun, Allan Kalungi, Richard Mayanja, Christopher Kintu, Ronald Makanga, Ayoub Kakande, Andrew Abaasa, Gershim Asiki, Robert Kalyesubula, Robert Newton, Moffat Nyirenda, Manj S. Sandhu, Pontiano Kaleebu
Journal: Cell Genomics (2022)

The Uganda Genome Resource (UGR) is a well-characterized genomic database with a range of phenotypic communicable and non-communicable diseases and risk factors generated from the Uganda General Population Cohort (GPC), a population-based open cohort established in 1989. The UGR comprises genotype data on ∼5,000 and whole-genome sequence data on ∼2,000 Ugandan GPC individuals from 10 ethno-linguistic groups. Leveraging other platforms at MRC/UVRI and LSHTM Uganda Research Unit, there is opportunity for additional sample collection to expand the UGR to advance scientific discoveries. Here, we describe UGR and highlight how it is providing opportunities for discovery of novel disease susceptibility genetic loci, refining association signals at new and existing loci, developing and testing polygenic scores to determine disease risk, assessing causal relations in diseases, and developing capacity for genomics research in Africa. The UGR has the potential to develop to a comparable level of European and Asian large-scale genomic initiatives.
Reconstructing mutational lineages in breast cancer by multi-patient-targeted single-cell DNA sequencing
Authors: Jake Leighton, Min Hu, Emi Sei, Funda Meric-Bernstam, Nicholas E. Navin
Journal: Cell Genomics (2022)

Single-cell DNA sequencing (scDNA-seq) methods are powerful tools for profiling mutations in cancer cells; however, most genomic regions sequenced in single cells are non-informative. To overcome this issue, we developed a multi-patient-targeted (MPT) scDNA-seq method. MPT involves first performing bulk exome sequencing across a cohort of cancer patients to identify somatic mutations, which are then pooled together to develop a single custom targeted panel for high-throughput scDNA-seq using a microfluidics platform. We applied MPT to profile 330 mutations across 23,500 cells from 5 patients with triple negative-breast cancer (TNBC), which showed that 3 tumors were monoclonal and 2 tumors were polyclonal. From these data, we reconstructed mutational lineages and identified early mutational and copy-number events, including early TP53 mutations that occurred in all five patients. Collectively, our data suggest that MPT can overcome a major technical obstacle for studying tumor evolution using scDNA-seq by profiling information-rich mutation sites.
2022 American College of Rheumatology/EULAR classification criteria for giant cell arteritis
Authors: Cristina Ponte, Peter C Grayson, Joanna C Robson, Ravi Suppiah, Katherine Bates Gribbons, Andrew Judge, Anthea Craven, Sara Khalid, Andrew Hutchings, Richard A Watts, Peter A Merkel, Raashid A Luqmani
Journal: Annals of the Rheumatic Diseases (2022)

Objective To develop and validate updated classification criteria for giant cell arteritis (GCA). Methods Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in six phases: (1) identification of candidate items, (2) prospective collection of candidate items present at the time of diagnosis, (3) expert panel review of cases, (4) data‐driven reduction of candidate items, (5) derivation of a points‐based risk classification score in a development data set and (6) validation in an independent data set. Results The development data set consisted of 518 cases of GCA and 536 comparators. The validation data set consisted of 238 cases of GCA and 213 comparators. Age ≥50 years at diagnosis was an absolute requirement for classification. The final criteria items and weights were as follows: positive temporal artery biopsy or temporal artery halo sign on ultrasound (+5); erythrocyte sedimentation rate ≥50 mm/hour or C reactive protein ≥10 mg/L (+3); sudden visual loss (+3); morning stiffness in shoulders or neck, jaw or tongue claudication, new temporal headache, scalp tenderness, temporal artery abnormality on vascular examination, bilateral axillary involvement on imaging and fluorodeoxyglucose–positron emission tomography activity throughout the aorta (+2 each). A patient could be classified as having GCA with a cumulative score of ≥6 points. When these criteria were tested in the validation data set, the model area under the curve was 0.91 (95% CI 0.88 to 0.94) with a sensitivity of 87.0% (95% CI 82.0% to 91.0%) and specificity of 94.8% (95% CI 91.0% to 97.4%). Conclusion The 2022 American College of Rheumatology/EULAR GCA classification criteria are now validated for use in clinical research.
Spatiotemporally resolved metabolomics and isotope tracing reveal CNS drug targets
Authors: Bo Jin, Xuechao Pang, Qingce Zang, Man Ga, Jing Xu, Zhigang Luo, Ruiping Zhang, Jiangong Shi, Jiuming He, Zeper Abliz
Journal: Acta Pharmaceutica Sinica B (2022)

Deconvolution of potential drug targets of the central nervous system (CNS) is particularly challenging because of the complicated structure and function of the brain. Here, a spatiotemporally resolved metabolomics and isotope tracing strategy was proposed and demonstrated to be powerful for deconvoluting and localizing potential targets of CNS drugs by using ambient mass spectrometry imaging. This strategy can map various substances including exogenous drugs, isotopically labeled metabolites, and various types of endogenous metabolites in the brain tissue sections to illustrate their microregional distribution pattern in the brain and locate drug action-related metabolic nodes and pathways. The strategy revealed that the sedative-hypnotic drug candidate YZG-331 was prominently distributed in the pineal gland and entered the thalamus and hypothalamus in relatively small amounts, and can increase glutamate decarboxylase activity to elevate γ-aminobutyric acid (GABA) levels in the hypothalamus, agonize organic cation transporter 3 to release extracellular histamine into peripheral circulation. These findings emphasize the promising capability of spatiotemporally resolved metabolomics and isotope tracing to help elucidate the multiple targets and the mechanisms of action of CNS drugs.
Transbronchial cryobiopsy: the right procedure for the right patient in the right place at the right time
Authors: Jeffrey L. Myers, Ulrich Costabel
Journal: European Respiratory Journal (2022)

<b>This editorial assesses the impact of newly published ERS guidelines for use of transbronchial cryobiopsy for diagnosis of interstitial lung disease, including future areas of research likely to facilitate ongoing global adoption</b>https://bit.ly/3LAy1n8
Epidemiologic Features of the Monkeypox Outbreak and the Public Health Response — United States, May 17–October 6, 2022
Authors: Christine Marie Kava, Dallas M. Rohraff, Bailey Wallace, Jennifer L. Mendoza-Alonzo, Dustin W. Currie, Anna E. Munsey, Nicole M. Roth, Jonathan Bryant-Genevier, Jordan L. Kennedy, Daniel L. Weller, Athalia Christie, Jennifer H. McQuiston, Peter Hicks, Penelope Strid, Emily Sims, Maria E. Negron, Kashif Iqbal, Sascha Ellington, Dawn K. Smith
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

On May 17, 2022, the Massachusetts Department of Health announced the first suspected case of monkeypox associated with the global outbreak in a U.S. resident. On May 23, 2022, CDC launched an emergency response (1,2). CDC's emergency response focused on surveillance, laboratory testing, medical countermeasures, and education. Medical countermeasures included rollout of a national JYNNEOS vaccination strategy, Food and Drug Administration (FDA) issuance of an emergency use authorization to allow for intradermal administration of JYNNEOS, and use of tecovirimat for patients with, or at risk for, severe monkeypox. During May 17-October 6, 2022, a total of 26,384 probable and confirmed* U.S. monkeypox cases were reported to CDC. Daily case counts peaked during mid-to-late August. Among 25,001 of 25,569 (98%) cases in adults with information on gender identity,† 23,683 (95%) occurred in cisgender men. Among 13,997 cisgender men with information on recent sexual or close intimate contact,§ 10,440 (75%) reported male-to-male sexual contact (MMSC) ≤21 days preceding symptom onset. Among 21,211 (80%) cases in persons with information on race and ethnicity,¶ 6,879 (32%), 6,628 (31%), and 6,330 (30%) occurred in non-Hispanic Black or African American (Black), Hispanic or Latino (Hispanic), and non-Hispanic White (White) persons, respectively. Among 5,017 (20%) cases in adults with information on HIV infection status, 2,876 (57%) had HIV infection. Prevention efforts, including vaccination, should be prioritized among persons at highest risk within groups most affected by the monkeypox outbreak, including gay, bisexual, and other men who have sex with men (MSM); transgender, nonbinary, and gender-diverse persons; racial and ethnic minority groups; and persons who are immunocompromised, including persons with advanced HIV infection or newly diagnosed HIV infection.
Tobacco Product Use Among Middle and High School Students — United States, 2022
Authors: Eunice Park-Lee, Chunfeng Ren, Maria Cooper, Monica Cornelius, Ahmed Jamal, Karen A. Cullen
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Tobacco use* is the leading cause of preventable disease, disability, and death among adults in the United States (1). Youth use of tobacco products in any form is unsafe, and nearly all tobacco use begins during youth and young adulthood (2). The Food and Drug Administration (FDA) and CDC analyzed data from the 2022 National Youth Tobacco Survey (NYTS) to estimate current (past 30-day) use of eight tobacco products among U.S. middle (grades 6-8) and high school (grades 9-12) students. In 2022, approximately 11.3% of all students (representing 3.08 million persons) reported currently using any tobacco product, including 16.5% of high school and 4.5% of middle school students (2.51 million and 530,000 persons, respectively). Electronic cigarettes (e-cigarettes) were the most commonly used tobacco product among high school (14.1%; 2.14 million) and middle school (3.3%; 380,000) students. Approximately 3.7% of all students (representing 1 million persons) reported currently smoking any combustible tobacco product. Current use of any tobacco product was higher among certain population groups, including 13.5% of non-Hispanic American Indian or Alaska Native (AI/AN)† students; 16.0% of students identifying as lesbian, gay, or bisexual (LGB); 16.6% of students identifying as transgender; 18.3% of students reporting severe psychological distress; 12.5% of students with low family affluence; and 27.2% of students with low academic achievement. Implementation of comprehensive evidence-based tobacco control strategies, combined with FDA regulation, is important for preventing and reducing youth tobacco product use (1,2).
Interim Recommendations from the Advisory Committee on Immunization Practices for the Use of Bivalent Booster Doses of COVID-19 Vaccines — United States, October 2022
Authors: Hannah G. Rosenblum, Megan Wallace, Monica Godfrey, Lauren E. Roper, Elisha Hall, Katherine E. Fleming-Dutra, Ruth Link-Gelles, Tamara Pilishvili, Jennifer Williams, Danielle L. Moulia, Oliver Brooks, H. Keipp Talbot, Grace M. Lee, Beth P. Bell, Matthew F. Daley, Sarah Meyer, Sara E. Oliver, Evelyn Twentyman
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Four COVID-19 vaccines are currently approved for primary series vaccination in the United States under a Biologics License Application or authorized under an emergency use authorization (EUA) by the Food and Drug Administration (FDA), and recommended for primary series vaccination by the Advisory Committee on Immunization Practices (ACIP): 1) the 2- or 3-dose monovalent mRNA BNT162b2 (Pfizer-BioNTech, Comirnaty) COVID-19 vaccine; 2) the 2- or 3-dose monovalent mRNA mRNA-1273 (Moderna, Spikevax) COVID-19 vaccine; 3) the single-dose adenovirus vector-based Ad26.COV.S (Janssen [Johnson & Johnson]) COVID-19 vaccine; and 4) the 2-dose adjuvanted, protein subunit-based NVX-CoV2373 (Novavax) COVID-19 vaccine. The number of doses recommended is based on recipient age and immunocompromise status (1). For additional protection, FDA has amended EUAs to allow for COVID-19 booster doses in eligible persons (1). Because COVID-19 vaccines have demonstrated decreased effectiveness during the period when the Omicron variant (B.1.1.529) of SARS-CoV-2 predominated, bivalent booster doses (i.e., vaccine with equal components from the ancestral and Omicron strains) were considered for the express purpose of improving protection conferred by COVID-19 vaccine booster doses (2). During September-October 2022, FDA authorized bivalent mRNA vaccines for use as a booster dose in persons aged ≥5 years who completed any FDA-approved or FDA-authorized primary series and removed EUAs for monovalent COVID-19 booster doses (1). Pfizer-BioNTech and Moderna bivalent booster vaccines each contain equal amounts of spike mRNA from the ancestral and Omicron BA.4/BA.5 strains. After the EUA amendments, ACIP and CDC recommended that all persons aged ≥5 years receive 1 bivalent mRNA booster dose ≥2 months after completion of any FDA-approved or FDA-authorized monovalent primary series or monovalent booster doses.
<i>Notes from the Field:</i> Outbreak of Ebola Virus Disease Caused by <i>Sudan ebolavirus</i> — Uganda, August–October 2022
Authors: Thomas Kiggundu, Alex R. Ario, Daniel Kadobera, Benon Kwesiga, Richard Migisha, Issa Makumbi, Daniel Eurien, Zainah Kabami, Joshua Kayiwa, Bernard Lubwama, Denis Okethwangu, Susan Nabadda, Godfrey Bwire, Sophia Mulei, Julie R. Harris, Emilio Dirlikov, Arthur G. Fitzmaurice, Sandra Nabatanzi, Yonas Tegegn, Allan N. Muruta, Daniel Kyabayinze, Amy L. Boore, Atek Kagirita, Henry Kyobe-Bosa, Henry G. Mwebesa, Diana Atwine, Jane R. Aceng Ocero, Natalie E. Brown, Brian Agaba, Sherry Rita Ahirirwe, Rebecca Akunzirwe, Alice Asio, Immaculate Atuhaire, Sarah Elayeete, Doreen Gonahasa, Edirisa Juniour Nsubuga, Patrick King, Saudah Kizito, Allan Komackech, Veronica Masanja, Stella Martha Migamba, Patience Mwine, Hellen Nelly Naiga, Petranilla Nakamya, Rose Nampeera, Mackline Ninsiima, Alex Ndybakira, Lawrence Oonyu, Brenda Nakafeero Simbwa, Hildah Tendo, Mercy Wendy Wanyana, Jane Frances Zalwango, Maria Gorette Zalwango, Robert Zavuga, Immaculate Asiimwe, Richardson Mafigiri, Esther Muwanguzi, Stephen Balinandi, Luke Nyakarahuka, Jimmy Baluku, Jackson Kyando, Alex Tumusiime, Caitlin Cossaboom, Carrie Eggers, John D. Klena, Lisa Nelson, Modupe Osinubi, Katrin Sadigh, Waverly Vosburgh, Mary-Claire Worrell, Philimon Kabagambe, Charles Okot, Godfrey Nsereko, Olivia Namusisi
Journal: MMWR Morbidity and Mortality Weekly Report (2022)
COVID-19–Associated Hospitalizations Among U.S. Infants Aged &lt;6 Months — COVID-NET, 13 States, June 2021–August 2022
Authors: Sarah Hamid, Kate Woodworth, Huong Pham, Jennifer Milucky, Shua J. Chai, Breanna Kawasaki, Kimberly Yousey-Hindes, Evan J. Anderson, Justin Henderson, Ruth Lynfield, Francesca Pacheco, Grant Barney, Nancy M. Bennett, Eli Shiltz, Melissa Sutton, H. Keipp Talbot, Andrea Price, Fiona P. Havers, Christopher A. Taylor, Jeremy Roland, Isaac Armistead, Carol Lyons, Kyle Openo, Lauren Leegwater, Erica Mumm, Mark Montoya, Kerianne Engesser, Sophrena Bushey, Nancy Moran, Nasreen Abdullah, Tiffanie Markus, Melanie Crossland
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

COVID-19-associated hospitalization rates are highest among adults aged ≥65 years (1); however, COVID-19 can and does cause severe and fatal outcomes in children, including infants (2,3). After the emergence of the SARS-CoV-2 B.1.1.529 (Omicron) BA.1 variant in December 2021, hospitalizations among children aged <5 years, who were ineligible for vaccination, increased more rapidly than did those in other age groups (4). On June 18, 2022, CDC recommended COVID-19 vaccination for infants and children aged ≥6 months (5). Data from the Coronavirus Disease 2019-Associated Hospitalization Surveillance Network (COVID-NET)* were analyzed to describe changes in the age distribution of COVID-19-associated hospitalizations since the Delta-predominant period (June 20-December 18, 2021)† with a focus on U.S. infants aged <6 months. During the Omicron BA.2/BA.5-predominant periods (December 19, 2021–August 31, 2022), weekly hospitalizations per 100,000 infants aged <6 months increased from a nadir of 2.2 (week ending April 9, 2022) to a peak of 26.0 (week ending July 23, 2022), and the average weekly hospitalization rate among these infants (13.7) was similar to that among adults aged 65-74 years (13.8). However, the prevalence of indicators of severe disease§ among hospitalized infants did not increase since the B.1.617.2 (Delta)-predominant period. To help protect infants too young to be vaccinated, prevention should focus on nonpharmaceutical interventions and vaccination of pregnant women, which might provide protection through transplacental transfer of antibodies (6).